Induced CD4+Foxp3+ Regulatory T Cells in Immune Tolerance (Annual Review of Immunology Book 30)

Immune Tolerance Neoplasms Infection. Immune system varicella-zoster immune globulin Thymic Tissue. Citations Publications citing this paper. Showing of extracted citations.

Adeegbe , Hiroyoshi Nishikawa Front. Re-educating immunity in respiratory allergies: Regulatory B and T cell responses in patients with autoimmune thyroid disease and healthy controls. Birte Kristensen Danish medical journal Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Goode Cancer immunology research References Publications referenced by this paper. Showing of references. A good example of division of labor between nTreg and iTreg cells. Intestinal bacterial colonization induces mutualistic regulatory T cell responses.

Thus, susceptibility to a relatively small handful of prenatal pathogens that exploit the physiological hole in host defense created by the reproductive process is probably the unfortunate byproduct of the greater good served by expanded maternal Tregs that sustain fetal tolerance Fig. Shifts in the balance between immune stimulation and suppression during pregnancy or following infection may dictate the immune pathogenesis of pregnancy complications after prenatal infection.

Another interesting example is the increased susceptibility to influenza A virus during pregnancy. Pregnant women have significantly higher rates of hospitalization, morbidity, and mortality after infection with either pandemic or seasonal influenza A strains Neuzil et al. Here, the newly recommended use of inactivated vaccine formulations during pregnancy provides an exceptional opportunity to characterize how pregnancy affects systemic immune responsiveness. Consistent with the notion of systemic immune moderation during pregnancy, reductions in vaccine-induced antibody titers among pregnant women compared with non-pregnant controls with both seasonal and pandemic inactivated influenza A vaccines have been described Schlaudecker et al.

Similarly, reduced antibody responses have been found among pregnant women after administration of the live attenuated vaccine for yellow fever virus Nasidi et al. However, it is also important to highlight that despite reductions in vaccine-induced influenza A antibody titers during pregnancy, these diminished responses nevertheless provide significant protection for both the mother and infant against respiratory infections, especially in resource-limited environments where influenza A virus is highly endemic Zaman et al.

These protective benefits of influenza A vaccination during pregnancy for subsequent infection and possibly fetal death have also recently been confirmed in more developed settings where influenza A virus is less prevalent Haberg et al.

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Together, these examples in which immune responsiveness to self-antigens, pathogens, and vaccination each are consistently dampened during pregnancy underscore the exceptional latent systemic immune modulatory properties that become unleashed with gestation.

At face value, these findings imply systemic shifts in the balance between immune suppression that averts autoimmunity and immune stimulation required for optimal host defense against infections beyond fetal tolerance become engaged with the accumulation of maternal Tregs during pregnancy. Along with these quantitative shifts between Tregs and non-Treg effector cells, modifications in Treg suppressive potency on a per cell basis can also occur Sakaguchi These qualitative shifts enable Tregs to more efficiently fine-tune the delicate balance between immune activation and suppression by rapidly responding to environmental cues.

This feature is probably most critical in the early stages after infection when the race between pathogen replication and immune activation has decisive impacts on the eventual outcome of infection. At the molecular level, this is consistent with drastic shifts in Treg suppressive potency induced by microbial ligands that stimulate cells through conserved pattern recognition receptors such as toll-like receptors.

For example, purified lipopolysaccharide LPS or flagellin stimulates increased Treg suppressive potency Caramalho et al.

Importantly, these shifts in Treg suppression after stimulation with individual microbial ligands in vitro parallel similar changes in suppressive potency after in vivo infection with intact pathogens, reflecting the cumulative response to multiple microbial ligands and the ensuing immune responses Minigo et al.

Applied to the unique physiological situation of pregnancy, in which immune tolerance to fetal antigens must be sustained, fractured tolerance stemming from disruptions in maternal Treg suppression may explain why fetal resorption occurs after systemic LPS administration, especially in mice lacking the immune regulatory cytokine IL10 Robertson et al.

Here, a specific role for maternal Tregs is supported by the protective properties of purified CD4 T cells that differentiate into Tregs with LPS-induced preterm delivery Bizargity et al. Thus, dampening maternal Treg suppression that unleashes the activation of innate or adaptive immune response pathways for optimal protection against infections has the potential to unravel the fine-tuned shifted balance between immune suppression and stimulation that maintains fetal tolerance during pregnancy.

In this regard, infection-induced disruption of maternal Treg suppression that fractures fetal tolerance may represent an underappreciated, but perhaps more unifying, pathway to explain the fundamental biology whereby pregnancy complications occur with clinically apparent or asymptomatic infections. Although the cause and effect relationships between maternal infection and unfortunate complications in human pregnancy including spontaneous abortion, stillbirth, and preterm labor have been described Andrews et al.

One important limitation has been the lack of representative animal models to specifically investigate pregnancy outcomes after infection. These limitations are somewhat bypassed in larger mammals including elegant descriptions of pregnancy in horses, sheep, and non-human primates Jobe , Barry et al.

However, the significantly more prolonged gestation time, relative lack of immunological tools and defined inbred strains, differences in placental architecture, and exponentially higher experimental costs impose other restrictions that are perhaps even more formidable. Furthermore, while human gestational cells and tissues have become more widely used to characterize the pathogenesis of prenatal infections Robbins et al.

Therefore, we propose combining the most salient aspects of individual models may represent the most efficient way to uncover the fundamental biology whereby pathogens cause prenatal infection and pregnancy complications. The additive and potential synergistic value is illustrated by recent complementary studies describing infection and pregnancy outcomes using the intracellular bacterium L. A somewhat surprising degree of resistance for placental cells to L.

In particular, human syncytiotrophoblasts that line the placental surface where nutrient and gas exchange occurs with direct exposure to maternal blood are highly resistant to bacterial invasion and intercellular spread Robbins et al. On the other hand, placental invasion primarily occurs through a substantially smaller subset of extravillous trophoblast cells that anchor the placenta in the uterine lining. However, even after invasion into extravillous trophoblast cells, profound defects in L. Interestingly, these protective properties of trophoblasts are not limited to only L.

Thus, placental cells provide a protective barrier to fetal infections, at least in vitro without the additional constraints imposed by the ensuing inflammatory response and maternal—fetal tolerance. In light of these innate cellular barriers to infections, it is interesting to reconsider the basic physiology that causes susceptibility to disseminated infections during pregnancy and the underlying mechanism whereby maternal infection triggers pregnancy complications. With regard to maternal susceptibility to disseminated infections, the prior dogma that placental and fetal tissues represent expanded target tissues susceptible to invasion seems less likely, given the finding that placental cells are actually very resistant to infections Abrahams et al.

Instead, given the necessity for maintaining fetal tolerance through sustained expansion of immune suppressive maternal Tregs, we propose active suppression by these cells may also play critical roles in causing maternal susceptibility to disseminated infection Fig.

Interestingly, however, since immunity against most infections is preserved during pregnancy, these do not appear to be drastic defects in global host defense and are instead more isolated holes that become exploited by pathogens with an established predisposition for infections during pregnancy.

Perhaps, more intriguing are the recent findings using allogeneic pregnancy in mice to investigate the pathogenesis of pregnancy complications triggered by disseminated maternal infection. Here, related studies using L. Unlike the necessity for distinct cell-intrinsic stimulation signals including the T-cell receptor signal 1 , co-stimulation signal 2 , and inflammatory cytokines signal 3 for T-cell activation shown using elegantly simplistic in vitro models Curtsinger et al.

Instead, transient reductions in Treg suppression that unleash the activation of protective immune effector cells following infection probably circumvent the need for some, but not all, more classical T-cell-intrinsic activation signals Ertelt et al. The importance of overriding Treg suppression for immune activation parallels the robust expansion of protective CD8 effector T cells in mice transiently ablated of Tregs after stimulation with purified peptides Ertelt et al.

Thus, infection- or inflammation-induced reductions in Treg suppression may represent a more fundamental signal zero for stimulating the activation of protective T effector cells Rowe et al. Applied to pregnancy when the sustained expansion of maternal Tregs is essential for maintaining fetal tolerance, infection- or inflammation-induced reductions in Treg suppression have the critical potential to fracture fetal tolerance with ensuing pregnancy complications Fig. This has been most definitively shown with a highly informative mating strategy using transgenic male mice that ubiquitously express defined model antigens to establish allogeneic pregnancy with non-transgenic female mice that transform model antigens into surrogate fetal antigens Erlebacher et al.

In turn, the robust expansion and activation of maternal T effector cells with fetal specificity with maternal infection recapitulate the quantitative accumulation and qualitative activation of these cells with maternal Treg ablation during pregnancy Rowe et al. Intriguingly, although fetal resorption with a reciprocal loss of live pups occurs in a dose-dependent fashion that parallels infection-induced reductions in maternal Treg suppression, bacteria could not be recovered from the majority of resorbed placental—fetal units after infection with low or intermediate dosages of virulent L.

These more recent findings suggesting a threshold inoculum is required for establishing sustained systemic infection are consistent with prior studies illustrating dose-dependent rates of placental invasion after i. Here, it is important to highlight that even attenuated L. Proposed model for how pregnancy complications may occur with or without direct pathogen invasion of the placental—fetal unit.

Infection-induced reductions in maternal Treg suppression that unleash the activation of protective immune components fracture fetal tolerance unmasking normally tolerized fetal antigens. In turn, inflammation occurs at the maternal—fetal interface containing the highest concentration of exposed fetal cells. With low-dosage infection a , the circulating pathogen is eradicated, but pregnancy complications ensue from damage caused by the activated maternal immune effector cells.

With high-dosage infection b , the persistence of circulating pathogen and inflammation at the maternal—fetal interface provides a conduit for invasion overriding the normally protective placental barrier. By showing that pregnancy complications can occur without direct bacterial invasion of the placental—fetal unit, the high frequency of pregnancy complications associated with L. On the other hand, since a majority of newborn infants are infected when born to mothers with disseminated infection Mylonakis et al.

We hypothesize inflammation at the maternal—placental interface induced by disrupted fetal tolerance may provide a more direct conduit drawing circulating bacteria into otherwise resistant placental cells.

Based on these findings with perinatal L. The more general applicability of this model now requires analogous studies with other pathogens that cause prenatal infections and pregnancy complications. In this regard, some clues for pathogens known to cause more severe systemic infections during pregnancy are already in place.

Similarly, quantitative reductions in peripheral Treg levels have been described in early stages after systemic murine cytomegalovirus and intestinal Toxoplasma gondii infections Li et al. If similar reductions in maternal Treg suppression were to occur with infection during pregnancy, disruptions in fetal tolerance with ensuing immune-mediated fetal wastage would be predicted. Unlike most other acute infections in which Treg suppression is reduced, increased proportions of activated Tregs with higher suppressive potency are found after Plasmodium infection, and these shifts are likely to minimize inflammatory sequelae at the expense of parasite replication Walther et al.

Nevertheless, given the necessity for sustained maternal Treg expansion in fetal tolerance, infection-induced qualitative or quantitative shifts in Treg suppression highlight a potentially more unifying pathway whereby maternal infection may trigger pregnancy complications. Reproduction and averting infections are arguably the two most dominant fundamental driving forces in nature. Adaptations that simultaneously improve both reproductive fitness and host defense are most ideal and should be strongly enriched for through positive selection.